Mitochondrial calcium cycling in neuronal function and neurodegeneration

Mitochondria are essential for proper cellular function through their critical roles in ATP synthesis, reactive oxygen species production, calcium (Ca(2+)) buffering, and apoptotic signaling. In neurons, Ca(2+) buffering is particularly important as it helps to shape Ca(2+) signals and to regulate numerous Ca(2+)-dependent functions including neuronal excitability, synaptic transmission, gene expression, and neuronal toxicity. Over the past decade, identification of the mitochondrial Ca(2+) uniporter (MCU) and other molecular components of mitochondrial Ca(2+) transport has provided insight into the roles that mitochondrial Ca(2+) regulation plays in neuronal function in health and disease. In this review, we discuss the many roles of mitochondrial Ca(2+) uptake and release mechanisms in normal neuronal function and highlight new insights into the Ca(2+)-dependent mechanisms that drive mitochondrial dysfunction in neurologic diseases including epilepsy, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. We also consider how targeting Ca(2+) uptake and release mechanisms could facilitate the development of novel therapeutic strategies for neurological diseases.